Neuroimmunophilln ligands are orally active small molecules which protect neuronal cells and can stimulate morphologic and functional recovery of injured axons in vitro and in vivo. Neurotrophic actions of these ligands have been demonstrated in neurons and axons in the central and peripheral nervous systems. These ligands are currently being evaluated in human clinical trials as treatments and therapies for neurodegenerative disorders, such as Parkinson's Disease. Another clinical trial utilizing GPI 1485 as a neuroprotective molecule to spare peripheral axons and maintain erectile function following bilateral nerve sparing prostatectomy is scheduled to begin in early 2003. Treatment of vulnerable peripheral neurons with these compounds may provide significant benefit to patients with painful peripheral neuropathy resulting from HIV infection and the ensuing treatment. However, the neurotrophic mechanism of action of this class of compounds is not well understood. In these studies, we propose to address the question of mechanism by identifying downstream binding targets of the GPI 1485-FKBP complex in neurons. We propose to use affinity chromatography and biochemical techniques to determine direct binding proteins of GPI 1485. We will complement these studies by evaluating mRNA and protein expression profiles in neuropathologic states following drug treatment. In addition, we will also evaluate the different biologic pathways utilized by neurotrophic FKBP and cyclophilin ligands. Cyclophilin ligands may act as neuroprotective molecules by interacting with cyclophilin D on the mitochondrial membrane. Therefore, we will also determine the protective role of cyclophilin ligands in mitochondrial dysfunction.